I-Corps: Curing inherited diseases at the source through next-generation clustered regularly interspaced short palindromic repeat (CRISPR) systems

这个I-Corps项目更广泛的影响/商业潜力是开发活细胞内编辑基因的技术。关键基因的突变是许多疾病的根本原因，从癌症到遗传性疾病，修复这些突变将显著改善患者的生活质量。此外，在细胞和生物体的基因组中以前所未有的精度进行位点特异性修饰，有可能彻底改变医学，农业，生物技术甚至基础研究实践。人类健康一直是大多数初步研究的主题，因为基因编辑第一次在广泛的衰弱性遗传疾病中具有治疗潜力，这些疾病目前只能通过数十年昂贵的治疗来解决。然而，目前的基因编辑计划主要集中在一组有限的遗传疾病上，主要是由CRISPR-Cas9的交付挑战所驱动。CRISPR-Cas9基因编辑的后期应用主要是离体的，而体内应用限于更易接近的器官靶点（例如，眼、肝）。该技术能够实现迄今为止对获取和潜在治愈存在重大未满足需求的疾病的挑战的目标。该I-Corps项目基于开发基因组编辑平台，该平台规避了CRISPR-Cas9目前的体内递送挑战。CRISPR/Cas9需要多种递送系统才能到达体内靶点，这可能导致高毒性和死亡。拟议的vCas系统由与Cas9不同的微型RNA引导基因组编辑器组成，包括世界上最紧凑和高效的CRISPR-Cas系统。vCas系统的大小约为Cas9的一半，为下一代基因组编辑工具提供了模板，这些工具可以很容易地包装在安全和现有的病毒载体中，以达到具有挑战性的体内治疗靶点。该方法已被证实可在哺乳动物细胞中产生高编辑效率，与现有技术相比，组件的尺寸非常小，有可能使以前无法治疗的遗传疾病更容易获得。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this I-Corps project is the development of technologies that edit genes within living cells. Mutations in critical genes are the underlying cause of many diseases, from cancer to hereditary disorders, and repairing these mutations would significantly improve patients’ quality of life. In addition, performing site-specific modifications at unprecedented precision in the genomes of cells and organisms offers the potential to revolutionize medicine, agriculture, biotechnology, and even basic research practices. Human health has been the subject of most initial studies as, for the first time, gene editing has curative potential in a wide range of debilitating genetic diseases that are currently only addressed via decades of costly treatment. However, current gene editing programs have been focused on a confined set of genetic diseases, primarily driven by delivery challenges with CRISPR-Cas9. Later-stage applications of CRISPR-Cas9 gene editing have been largely ex vivo, with in vivo applications limited to more accessible organ targets (e.g., eye, liver). The proposed technology has the capacity to reach targets that to date have been a challenge to access and potentially cure diseases for which there is significant unmet need.This I-Corps project is based on the development of a genome editing platform that circumvents current in vivo delivery challenges with CRISPR-Cas9. CRISPR/Cas9 requires multiple delivery systems to reach in vivo targets, which may lead to high toxicity and death. The proposed vCas systems consist of miniature RNA-guided genome editors distinct from Cas9, including the world’s most compact and highly efficient CRISPR-Cas systems. At approximately half the size of Cas9, vCas systems provide a template for next-generation genome editing tools that may be easily packaged in safe and existing viral vectors to reach challenging in vivo therapeutic targets. The proposed approach has been validated to generate high editing efficiency in mammalian cells, and the extremely small size of the components compared to existing technologies has the potential to render previously untreatable genetic diseases more accessible.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.